Impact of proton pump inhibitors on immunotherapy is modulated by prior chemotherapy and linked to gut microbiome-immune cell signatures.

PPI use was associated with shorter overall survival in patients with advanced cancers treated with immune checkpoint inhibitors.

• Retrospective study included n=1078 patients with advanced cancer treated with ICIs.
• The association between PPI use and shorter OS was statistically significant across the cohort.
• The strongest effects of PPI use on OS were seen in melanoma patients.
• Survival analyses were used to evaluate associations between PPI use and clinical outcomes.

PPI use was associated with altered microbiome composition in patients treated with immune checkpoint inhibitors.

• Stool samples from melanoma patients treated with ICIs (n=42) were analyzed for microbiome composition.
• Stool and blood samples from patients with NSCLC and renal cell carcinoma treated with ICIs (n=8) were also analyzed.
• Microbiome composition was assessed using metagenomic whole-genome shotgun sequencing.
• Diversity metrics and multivariable models were used to evaluate associations between PPI use and microbiome alterations.
• Prospective study data implicated PPI use as having an effect on the microbiome.

PPI use was associated with altered immune cell populations in patients treated with immune checkpoint inhibitors.

• Immune cell populations from blood samples were determined using CyTOF (mass cytometry).
• Blood samples were collected from patients with NSCLC and renal cell carcinoma treated with ICIs (n=8).
• Associations between PPI use and immune cell composition were evaluated using multivariable models.
• The study identified gut microbiome-immune cell signatures linked to PPI use.

The impact of PPI use on immunotherapy outcomes was modulated by prior chemotherapy.

• Prior chemotherapy was identified as a modulating factor in the relationship between PPI use and ICI outcomes.
• This modulation by prior chemotherapy was highlighted as a key finding in the study title and conclusions.
• The study evaluated this interaction in the context of a retrospective cohort of n=1078 patients with advanced cancer.

PPIs are among the most widely used medications worldwide and have been previously associated with altered microbiomes relevant to immune checkpoint inhibitor response.

• The study was motivated by PPIs being 'one of the most widely used medications in the world.'
• Prior evidence had demonstrated an association between PPI use and altered microbiome.
• The microbiome has been demonstrated to be important for ICI response.
• The study sought to determine whether PPI use was associated with shorter OS and whether changes were linked to altered microbiomes and immune cell composition.